EP1007527B1 - Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same - Google Patents

Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same Download PDF

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EP1007527B1
EP1007527B1 EP98941567A EP98941567A EP1007527B1 EP 1007527 B1 EP1007527 B1 EP 1007527B1 EP 98941567 A EP98941567 A EP 98941567A EP 98941567 A EP98941567 A EP 98941567A EP 1007527 B1 EP1007527 B1 EP 1007527B1
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compound
general formula
formula
represented below
product
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EP1007527A1 (en
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Jean-Bernard Cazaux
Olivier Lavergne
Christine Le Breton
Eric Lotissement "Les Sabines" MANGINOT
Dennis Bigg
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Ipsen Pharma SAS
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Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Camptothecin is a natural compound that was first isolated from the leaves and bark of the Chinese plant called camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88: 3888 (1966)) .
  • Camptothecin is a pentacyclic compound consisting of an indolizino [1,2-b] quinoline fragment fused with a six-chain ⁇ -hydroxylactone.
  • the carbon at position 20, which carries the ⁇ -hydroxy group, is asymmetric and gives the molecule a rotary power.
  • the natural form of camptothecin has the absolute "S" configuration at carbon 20 and corresponds to the following formula:
  • Camptothecin has anti-proliferative activity in several lines cancer cells, including human tumor cell lines from colon, lung and breast (Suffness, M. et al .: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). We suggest that the anti-proliferative activity of camptothecin is related to its activity topoisomerase I inhibitor of DNA.
  • camptothecins New Anticancer Agents, Putmesil, M., et al., P. 27 (CRC Press, 1995); Wall, M. et al., Cancer Res. 55: 753 (1995); Hertzberg et al., J. Med. Chem. 32: 715 (1982), and Crow et al. J. Med. Chem. 35: 4160 (1992)). More recently, the Applicant has developed a new class of camptothecin analogues (cf. patent application WO 97/00876), in which a ⁇ -hydroxylactone replaces the natural ⁇ -hydroxylactone of camptothecin or its derivatives as described in US Patent 5,459,269.
  • the subject of the invention is a new process for preparing an intermediate for enantiomerically pure synthesis, as well as new analogues enantiomerically pure camptothecin.
  • the invention therefore firstly relates to new camptothecin analogs which differ from any known compound, characterized in that they have the formula (II) represented below or in that they are salts of the compound of formula (II) such as for example that of formula (III) represented below
  • a key intermediate in the synthesis of this type of optically pure compound is a product of general formula M shown above in which R represents a linear or branched alkyl radical containing from 1 to 10 carbon atoms.
  • R represents an ethyl radical.
  • a nucleophile such as compound M
  • a deprotonated derivative thereof by treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example the diethyl or diisopropyl azodicarboxylate
  • an aprotic solvent such as, for example, tetrahydrofuran or N, N- dimethylformamide.
  • the cyclization of the compound O 2 to give the compound of formula (II) is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under basic conditions (provided for example by an alkaline acetate optionally combined with a phase transfer agent such as for example tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N, N- dimethylformamide, at a temperature between 50 ° C and 120 ° C (R. Grigg and coll., Tetrahedron 46, page 4003 (1990)).
  • a palladium catalyst for example palladium diacetate
  • basic conditions provided for example by an alkaline acetate optionally combined with a phase transfer agent such as for example tetrabutylammonium bromide
  • an aprotic solvent such as acetonitrile or N, N- dimethylformamide
  • the invention also provides a compound of general formula M as defined above. This product can be used for the manufacture of medicines.
  • the compound of formula N 2 can be obtained according to the following process: the aniline of formula P 2 represented below is ortho-acylated by reaction with chloroacetonitrile in the presence of boron trichloride and another Lewis acid such as aluminum trichloride, titanium tetrachloride or diethylaluminum chloride in an aprotic solvent or an aprotic solvent mixture , followed by hydrolysis (see Sugasawa, T, et al. J. Am. Chem. Soc. 100 , p. 4842 (1978)).
  • the intermediate thus obtained is then treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated with an alkaline alcoholate, for example sodium methylate in methanol , to give ethyl 7-chloro-4-chloromethyl-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.
  • the latter is transformed into ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate by treatment with phosphoryl oxychloride.
  • Nucleophilic substitution is then carried out by treatment with 4-methylpiperidine.
  • the ethyl carboxylate function is then reduced by diisobutylaluminum hydride in an aprotic solvent such as dichloromethane to give the compound of formula N 2 . You can optionally reverse the order of the last two steps.
  • the compound of formula ( II ) can be transformed into a pharmaceutically acceptable salt according to the usual methods.
  • Acceptable salts include, by way of example and without limitation, addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acids such as acetate, maleate, fumarate , tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate.
  • inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate
  • organic acids such as acetate, maleate, fumarate , tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and
  • the compounds of the present invention have interesting properties pharmacological. This is how the compounds of the present invention have an activity topoisomerase I and II inhibitor and anti-tumor activity. The state of technique suggests that the compounds of the invention exhibit anti-parasitic activity and / or anti-viral. The compounds of the present invention can thus be used in different therapeutic applications.
  • the compounds can inhibit topoisomerase, for example of type I and II, in a patient, for example a mammal such as the man, by administration to this patient of a therapeutically effective quantity of a compound of formula ( I ) or of formula ( II ), or of a pharmaceutically acceptable salt of a compound of formula ( II ), or of any mixture thereof.
  • the compounds of the invention have anti-tumor activity. They can be used for the treatment of tumors, for example tumors expressing a topoisomerase, in a patient by administration to said patient of a therapeutically effective amount of a compound of formula ( II ), or of a pharmaceutically acceptable salt of a compound of formula ( II ), or of any mixture of the latter.
  • tumors or cancers include cancers of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix uteri, endometrium corpus, ovaries, prostate, testes, bladder, kidneys, liver, pancreas, bones, connective tissue, skin, eyes, brain and central nervous system, as well than thyroid cancer, leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myelomas and others.
  • They can also be used for the treatment of parasitic infections by inhibition of hemoflagellates (for example in trypanosomy or infections leishmania) or by inhibition of the plasmodia (as for example in malaria), but also the treatment of viral infections or diseases.
  • the present application also relates, as medicaments, to the product of formula ( II ) as defined above, or to the addition salts with pharmaceutically acceptable inorganic or organic acids of the product of formula ( II ) such as for example the salt of formula ( III ) previously described, or alternatively any mixture of the latter.
  • the invention likewise relates to pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.
  • the invention thus relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid additive salt thereof, in association with a pharmaceutically acceptable carrier according to the mode chosen administration (e.g. oral, intravenous, intraperitoneal, intramuscular, trans-dermal or subcutaneous).
  • a pharmaceutically acceptable carrier e.g. oral, intravenous, intraperitoneal, intramuscular, trans-dermal or subcutaneous.
  • the pharmaceutical composition can be in solid, liquid, liposome or micelle form lipid.
  • the pharmaceutical composition can be in solid form such as, for example, powders, pills, granules, tablets, liposomes, capsules or suppositories.
  • the pill, the tablet or capsule may be coated with a substance capable of protecting the composition of the action of stomach acid or enzymes in the stomach of the subject for a period of time sufficient to allow this composition to pass non digested in the small intestine of the latter.
  • the compound can also be administered locally, for example at the site of the tumor.
  • the compound can also be administered using the extended release process (e.g. extended release or infusion pump).
  • the appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, carbonate magnesium, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
  • Pharmaceutical compositions containing a compound of the invention can therefore also be in liquid form such as, for example, solutions, emulsions, suspensions or extended release formulation.
  • Media suitable liquids can be, for example, water, organic solvents such as glycerol or glycols such as polyethylene glycol, as well as their mixtures, in various proportions, in water.
  • a subject of the invention is also the use of the product of formula (II) as defined above, or of the addition salts with pharmaceutically acceptable mineral or organic acids of the product of formula (II) , such as for example the salt of formula (III) previously described, or a mixture of the latter, for the preparation of medicaments intended to inhibit topoisomerases, and more particularly topoisomerases type I or type II, of medicaments intended to treat tumors, drugs to treat parasitic infections, and drugs to treat viral infections or diseases.
  • the dose of a compound according to the present invention varies according to the mode of administration, age and the body weight of the subject to be treated as well as the state of the latter, and it will be decided in final by the attending physician or veterinarian. Such an amount determined by the the attending physician or veterinarian is referred to herein as a "therapeutically effective amount”.
  • the retention times obtained are 6.4 minutes for the (-) enantiomer and 2.8 minutes for the (+) enantiomer.
  • the report enantiomer (-) / enantiomer (+) is 83/17.
  • step 1.a The solution in isopropyl alcohol of the quinidine salt of the (-) enantiomer of the acid 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic (step 1.a) is concentrated.
  • the concentrate is taken up in 270 ml of methylene chloride and 270 ml of a 1N hydrochloric acid solution.
  • the reaction medium is stirred for 16 hours at 20 ° C. After decantation, the organic phase is concentrated, the concentrate is taken up in methanol to be used in the next phase.
  • Example 2 ( + ) -chloride of 1- [9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H, 3H-oxepino [ 3 ', 4': 6,7] indolizino [1,2-b] quinolin-12-ylmethyl] -4-methyl-hexahydropyridinium
  • reaction medium is then carefully hydrolyzed using 2N hydrochloric acid (240 ml) and the mixture is heated at reflux for 1 h.
  • Water (1 l) and ethyl acetate (1 l) are added, the mixture obtained is stirred for 15 min before separating the phases.
  • the aqueous phase is again extracted with ethyl acetate (200 ml), and the combined organic phases are washed with water (500 ml). It is dried over magnesium sulfate and the organic phase is concentrated.
  • the residue is taken up in petroleum ether (fraction having a boiling point of 45 to 60 ° C; 150 ml) and the mixture thus obtained is left to stand for 16 h at 4 ° C.
  • step 3.a 25 g; 0.11 mol
  • triethylamine 30.6 ml; 0.22 mol
  • acetonitrile 520 ml
  • Ethylmalonyl chloride (28.1 ml; 0.22 mol) is added at room temperature and under an argon atmosphere.
  • the mixture obtained is stirred for 3 h.
  • Sodium ethanolate (prepared by dissolving 3 g, ie 0.13 mol, of sodium in 140 ml of absolute ethanol) is then added dropwise and the resulting mixture is stirred at room temperature for 16 h.
  • the precipitate is recovered by filtration, washed successively with ethanol, water, ethanol and ether.
  • step 3.b Product from step 3.b (28.4 g; 90 mmol) is heated for 4 h at reflux in phosphorus oxychloride (400 ml). The mixture obtained is concentrated under reduced pressure (20 mm Hg) at 80 ° C. The residue is taken up in diisopropyl ether (400 ml). The resulting precipitate is recovered by filtration, washed with ether and petroleum ether, then dried under reduced pressure to give the title product (25.4 g; 85% yield) in the form of a powder whitish (P f 126-127 ° C).
  • the aqueous phase is extracted with ethyl acetate (200 ml) and the combined organic phases are washed with an aqueous solution of sodium chloride (concentrated to 20% by weight; 500 ml).
  • the organic phase obtained is dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the residue is taken up in diethyl ether (50 ml) and the resulting precipitate is recovered by filtration. By drying under reduced pressure, the title product is obtained (18.3 g; 93% yield) as a white powder (P f 169-170 ° C).
  • the resulting precipitate is recovered by filtration and washed successively with acetonitrile, water, acetone and diethyl ether to give, after drying under reduced pressure, the title product (2, 5 g; 70% yield) in the form of a whitish powder.
  • a mixture of product from step 3.g (2.3 g; 7.7 mmol) and absolute ethanol (300 ml) is subjected for 2 minutes to ultrasound.
  • the milky suspension obtained is stirred and treated with hydrochloric acid (1N solution; 13.2 ml; 13.2 mmol) to give a light yellow solution which, on standing, forms a gel-like precipitate.
  • the precipitate is recovered by filtration on Büchner and washed successively with ethanol and ether, then dried under reduced pressure to give the title product (2.1 g; 85% yield).
  • SW620 human colon adenocarcinoma
  • OVCAR-5 human ovarian adenocarcinoma
  • PC-3 and DU 145 human prostate cell line
  • NCI-H69 human adenocarcinoma human lung.
  • SW620 human colon adenocarcinoma
  • OVCAR-5 human ovarian adenocarcinoma
  • PC-3 and DU 145 human prostate cell line
  • NCI-H69 human adenocarcinoma human lung.
  • These lines come from the NCI / Frederick Cancer Research and Development Center (Frederick, MD). They are cultured in complete medium comprising the RMPI-1640 medium enriched with 10% fetal calf serum and 2 mM L-Glutamine. They are incubated at 37 ° C in a humid atmosphere at 5% CO 2 .
  • the adherent cells are detached by treatment with a 0.25% trypsin and 0.2% EDTA solution (Worthington Biochemical Corp., Freehold, NJ) for 5 minutes at 37 ° C.
  • the cells are counted using a Coulter Z1 counter (Coulter Corp., Hialeah, FL). Viability is assessed by staining the cells with propidium iodide and then counting them with an EPICS Elite flow cytometer (Coulter).
  • Example 2 The compound of Example 2 to be tested is dissolved at 5 mM in a solution of N, N-dimethylacetamine (DMA, Aldrich). Subsequent dilutions are made with culture medium. The final molar concentrations tested were: 1.10 -6 2.10 -7, -8 4.10 8.10 -9, -9 1.6.10, 3,2.10 -10, 6,4.10 -11, -11 1,28.10, 2,56.10 -12 , and 5,12.10 -13 . Each concentration is tested on eight wells. Checks on the influence of DMA were carried out on all the cell lines. It follows from these checks that at the maximum concentration used (0.02%) DMA has no effect. Doxorubicin at concentrations of 1.10 -7 M and 2.10 -7 M is used as a positive control.
  • DMA N, N-dimethylacetamine
  • the cells are seeded at 5.10 3 cells per well on a 96-well microplate (Costar Corporation, Cambridge, MA). The cells are incubated 24 h at 37 ° C to allow resumption of cell multiplication. The compound of Examples 2 and 3 to be tested is then added at the concentrations indicated above and the cells are incubated at 37 ° C. in a humid atmosphere at 5% CO 2 , for 3 days for the adherent cells (SW620, OVCAR-5 , PC-3 and DU 145) and for 5 days for cells in suspension (NCI-H69).
  • the adherent cells are tested by the SRB method (described by LV Rubenstein, RH Shoemaker, KD Paull, RM Simon, S. Tosini, P. Skehan, DA Scudiero., A. Monks, and MR Boyd "Comparison of in vitro anticancer- drug-screening data generated with tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines ", J. Nat. Cancer Inst ., 82 : 1113-1118, 1990). After three days of incubation, the supernatant is eliminated and 200 ⁇ l RPMI-1640 free of fetal calf serum is added.
  • the cells are fixed by adding 50 ⁇ l of 50% trichloroacetic acid (final concentration of 10% trichloroacetic acid) and incubated at 4 ° C for 1 hour.
  • the wells are washed 5 times with water and then stained with 50 ⁇ l of a 0.4% solution of sulforhodamine B (SRB, Sigma) in 1% acetic acid at room temperature for 10 minutes.
  • SRB sulforhodamine B
  • the dye is dissolved with 100 ⁇ l of 10 mM TRIS buffer, pH 10, for approximately 5 minutes with stirring, the microplates are read by spectrophotometry at 570 nm.
  • the cells in suspension are tested by the XTT method (described by DA Scudiero, RH Shoemaker, KD Paull, A. Monks, S. Tierney, TH Nofziger, MJ Currens, D. Seniff and MR Boyd: "Evaluation of a soluble tetrazolium / formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines ", Cancer Research 48 : 4827-4833, 1988).
  • the XTT sodium salt of 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5-carboxanilide, (Sigma)
  • phenazine methosulfate PMS, Sigma
  • the final concentrations of XTT and PMS are 50 and 0.38 ⁇ g / well, respectively.
  • the production of formazan is stopped by adding 10 ⁇ l of 10% sodium dodecylsulfate (Sigma) and the absorbance is read by spectrophotometry at 450 nm with a reference filter at 600-650 nm.
  • Example 2 The molar concentrations of the compounds of Example 2 which inhibit cell proliferation by 50% are compiled in the following table: Cell line Example 2 SW620 3.10 -8 OVCAR-5 4.10 -8 PC-3 3.10 -8 FROM 145 7.10 -9 NCI-H69 1.10 -9

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Abstract

The invention concerns novel camptothecin analogues and in particular products corresponding to the following formulae: (+)-5-ethyl-9, 10-difluoro-5-hydroxy-4, 5,13,15-tetrahydro-1H, 3H-oxepino[3',4':6, 7]indolizino[1,2-b] quinoline-3,15-dione; (+)-1-[9-chloro-5- ethyl-5-hydroxy-10-methyl-3, 15-dioxo-4,5,13, 15-tetrahydro-1H,3H-oxepinol[3' ,4':6,7]indolizino [1,2-b]quinoline-12-ylmethyl] -4-methyl-hexahydropyridinium chloride; their application as medicine, pharmaceutical compositions containing them and their use for producing antitumoral, antiviral or antiparasitic medicines. The invention also concerns a novel synthesis intermediate of said products and a method for preparing said intermediate.

Description

La camptothécine est un composé naturel qui a été isolé pour la première fois des feuilles et de l'écorce de la plante chinoise appelée camptotheca acuminata (voir Wall et ses collaborateurs, J. Amer. Chem. Soc. 88:3888 (1966)). La camptothécine est un composé pentacyclique constitué d'un fragment indolizino[1,2-b]quinoléine fusionné avec une α-hydroxylactone à six chaínons. Le carbone en position 20, qui porte le groupe α-hydroxy, est asymétrique et confère à la molécule un pouvoir rotatoire. La forme naturelle de la camptothécine possède la configuration absolue "S" au carbone 20 et répond à la formule suivante :

Figure 00010001
Camptothecin is a natural compound that was first isolated from the leaves and bark of the Chinese plant called camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88: 3888 (1966)) . Camptothecin is a pentacyclic compound consisting of an indolizino [1,2-b] quinoline fragment fused with a six-chain α-hydroxylactone. The carbon at position 20, which carries the α-hydroxy group, is asymmetric and gives the molecule a rotary power. The natural form of camptothecin has the absolute "S" configuration at carbon 20 and corresponds to the following formula:
Figure 00010001

La camptothécine présente une activité anti-proliférative dans plusieurs lignées cellulaires cancéreuses, comprenant les lignées cellulaires de tumeurs humaines du colon, du poumon et du sein (Suffness, M. et collaborateurs : The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). On suggère que l'activité anti-proliférative de la camptothécine est en relation avec son activité inhibitrice de la topoisomérase I de l'ADN.Camptothecin has anti-proliferative activity in several lines cancer cells, including human tumor cell lines from colon, lung and breast (Suffness, M. et al .: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). We suggest that the anti-proliferative activity of camptothecin is related to its activity topoisomerase I inhibitor of DNA.

Il a été indiqué que l'α-hydroxylactone était une exigence absolue à la fois pour l'activité in vivo et in vitro de la camptothécine (Camptothecins : New Anticancer Agents, Putmesil, M., et ses collaborateurs, ed., p. 27 (CRC Press, 1995) ; Wall, M. et ses collaborateurs, Cancer Res. 55:753 (1995); Hertzberg et ses collaborateurs, J. Med. Chem. 32:715 (1982) et Crow et. ses collaborateurs; J. Med. Chem. 35:4160 (1992)). Plus récemment, la demanderesse a mis au point une nouvelle classe d'analogues de la camptothécine (cf. demande de brevet WO 97/00876), dans lesquels une β-hydroxylactone remplace l'α-hydroxylactone naturelle de la camptothécine ou de ses dérivés tels que décrits dans le brevet US 5 459269. It has been reported that α-hydroxylactone is an absolute requirement for both in vivo and in vitro activity of camptothecin (Camptothecins: New Anticancer Agents, Putmesil, M., et al., P. 27 (CRC Press, 1995); Wall, M. et al., Cancer Res. 55: 753 (1995); Hertzberg et al., J. Med. Chem. 32: 715 (1982), and Crow et al. J. Med. Chem. 35: 4160 (1992)). More recently, the Applicant has developed a new class of camptothecin analogues (cf. patent application WO 97/00876), in which a β-hydroxylactone replaces the natural α-hydroxylactone of camptothecin or its derivatives as described in US Patent 5,459,269.

L'invention a pour objet un nouveau procédé de préparation d'un intermédiaire de synthèse énantiomériquement pur, ainsi que de nouveaux analogues énantiomériquement purs de la camptothécine.The subject of the invention is a new process for preparing an intermediate for enantiomerically pure synthesis, as well as new analogues enantiomerically pure camptothecin.

L'invention a donc d'abord pour objet de nouveaux analogues de la camptothécine qui diffèrent de tout composé connu, caractérisés en ce qu'ils ont la formule (II) représentée ci-dessous

Figure 00020001
ou en ce qu'il s'agit de sels du composé de formule (II) tel par exemple celui de formule (III) représentée ci-dessous
Figure 00020002
The invention therefore firstly relates to new camptothecin analogs which differ from any known compound, characterized in that they have the formula (II) represented below
Figure 00020001
or in that they are salts of the compound of formula (II) such as for example that of formula (III) represented below
Figure 00020002

Un intermédiaire-clé dans la synthèse de ce type de composés optiquement purs est un produit de formule générale M représentée ci-dessus

Figure 00030001
dans laquelle R représente un radical alkyle linéaire ou ramifié comptant de 1 à 10 atomes de carbone. De préférence, R représente un radical éthyle.A key intermediate in the synthesis of this type of optically pure compound is a product of general formula M shown above
Figure 00030001
in which R represents a linear or branched alkyl radical containing from 1 to 10 carbon atoms. Preferably, R represents an ethyl radical.

Le composé de formule (II) peut être préparé de la façon suivante :

  • on couple le composé de formule
    Figure 00030002
avec un composé de formule N2 représentée ci-dessous :
Figure 00030003
pour donner le composé de formule O2 :
Figure 00040001
la cyclisation du composé O2 donne le composé de formule (II), lequel peut, après salification, donner le composé de formule (III).The compound of formula (II) can be prepared in the following way:
  • we couple the compound of formula
    Figure 00030002
with a compound of formula N 2 shown below:
Figure 00030003
to give the compound of formula O 2 :
Figure 00040001
the cyclization of the compound O 2 gives the compound of formula ( II ), which can, after salification, give the compound of formula ( III ).

La formation du composé O2 à partir du composé de formule générale M pour lequel R représente un radical éthyle et N2 s'effectue par un traitement connu de l'homme de l'art sous le nom de réaction de Mitsunobu (se référer à Mitsunobu, O. et coll. Synthesis, p.1 (1981)). Il s'agit de déplacer la fonction hydroxyle du composé N par un nucléophile tel que le composé M, ou un dérivé déprotoné de ce dernier, par un traitement avec une phosphine, par exemple la triphénylphosphine, et un dérivé azodicarboxylate, par exemple l'azodicarboxylate de diéthyle ou de diisopropyle, dans un solvant aprotique tel que, par exemple, le tétrahydrofurane ou le N,N-diméthylformamide. La cyclisation du composé O2 pour donner le composé de formule (II) s'effectue de préférence en présence d'un catalyseur palladié (par exemple le diacétate de palladium) dans des conditions basiques (fournies par exemple par un acétate alcalin éventuellement combiné à un agent de transfert de phase tel que par exemple le bromure de tétrabutylammonium), dans un solvant aprotique tel que l'acétonitrile ou le N,N-diméthylformamide, à une température comprise entre 50° C et 120° C (R. Grigg et coll., Tetrahedron 46, page 4003 (1990)).The formation of the compound O 2 from the compound of general formula M for which R represents an ethyl radical and N 2 is carried out by a treatment known to those skilled in the art under the name of Mitsunobu reaction (refer to Mitsunobu, O. et al. Synthesis , p.1 (1981)). This involves displacing the hydroxyl function of compound N by a nucleophile such as compound M, or a deprotonated derivative thereof, by treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example the diethyl or diisopropyl azodicarboxylate, in an aprotic solvent such as, for example, tetrahydrofuran or N, N- dimethylformamide. The cyclization of the compound O 2 to give the compound of formula (II) is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under basic conditions (provided for example by an alkaline acetate optionally combined with a phase transfer agent such as for example tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N, N- dimethylformamide, at a temperature between 50 ° C and 120 ° C (R. Grigg and coll., Tetrahedron 46, page 4003 (1990)).

L'invention offre également, un composé de formule générale M tel que défini précédemment. Ce produit peut être utilisé pour la fabrication de médicaments. The invention also provides a compound of general formula M as defined above. This product can be used for the manufacture of medicines.

Le composé de formule M est synthétisé selon un procédé nouveau faisant partie de l'invention et constitué des étapes successives suivantes :

  • l'ester t-butylique racémique représenté ci-dessous
    Figure 00060001
    (pour sa préparation, se référer notamment à la demande de brevet WO 97/00876) est traité par de l'acide trifluoroacétique durant 18 h à température ambiante pour donner l'acide carboxylique correspondant ;
  • on chauffe dans de l'alcool isopropylique le sel de quinidine de l'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque à une température supérieure à 30 °C, et de préférence de 50 °C environ, avant de laisser refroidir le milieu réactionnel jusqu'à température ambiante, de sorte que le sel de l'énantiomère (+) de l'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque cristallise tandis que le sel de l'isomère (-), dont l'anion est représenté ci-dessous, reste en solution
    Figure 00060002
  • la solution dans l'alcool isopropylique du sel de l'énantiomère (-) de l'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque est concentrée et traitée à l'acide chlorhydrique et agitée, donnant le composé de formule A' représentée ci-dessous
    Figure 00070001
  • le composé A' est ensuite mis en contact avec du palladium sur charbon humide, puis on ajoute du formiate d'ammonium ou de l'acide formique au mélange pour donner le produit débenzylé B' représenté ci-dessous
    Figure 00070002
  • on cyclise ensuite le composé de formule B' par action de dicyclohexylcarbodiimide pour obtenir le composé lactonique de formule C' représentée ci-dessous
    Figure 00070003
  • enfin, on transforme le groupement -OCH3 du composé lactonique de formule C' en carbonyle, par action d'iodure de sodium et de chlorure de triméthylsilyle, pour obtenir la (+)-5-éthyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino[3,4-c]pyridin-3,9-dione (ou (+)-EHHOPD) représenté ci-dessous.
    Figure 00080001
The compound of formula M is synthesized according to a new process forming part of the invention and consisting of the following successive stages:
  • the racemic t- butyl ester shown below
    Figure 00060001
    (for its preparation, refer in particular to patent application WO 97/00876) is treated with trifluoroacetic acid for 18 h at room temperature to give the corresponding carboxylic acid;
  • the quinidine salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic acid is heated in isopropyl alcohol to a temperature above 30 ° C., and preferably of 50 ° C approximately, before allowing the reaction medium to cool to room temperature, so that the salt of the (+) enantiomer of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) acid - 3-hydroxy-pentanoic crystallizes while the salt of the (-) isomer, the anion of which is shown below, remains in solution
    Figure 00060002
  • the solution in isopropyl alcohol of the salt of the (-) enantiomer of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic acid is concentrated and treated with hydrochloric acid and stirred, giving the compound of formula A ' shown below
    Figure 00070001
  • compound A ' is then brought into contact with palladium on wet charcoal, then ammonium formate or formic acid is added to the mixture to give the debenzylated product B' shown below
    Figure 00070002
  • then the compound of formula B ' is cyclized by the action of dicyclohexylcarbodiimide to obtain the lactonic compound of formula C' shown below
    Figure 00070003
  • finally, the -OCH 3 group of the lactonic compound of formula C ' is transformed into carbonyl, by the action of sodium iodide and trimethylsilyl chloride, to obtain the (+) - 5-ethyl-5-hydroxy-1,3 , 4,5,8,9-hexahydrooxépino [3,4-c] pyridin-3,9-dione (or (+) - EHHOPD ) shown below.
    Figure 00080001

Le composé de formule N2 peut être obtenu selon le procédé suivant : l'aniline de formule P2 représentée ci-dessous

Figure 00090001
est ortho-acylée par réaction avec le chloroacétonitrile en présence de trichlorure de bore et d'un autre acide de Lewis tel que le trichlorure d'aluminium, le tétrachlorure de titane ou le chlorure de diéthylaluminium dans un solvant aprotique ou un mélange de solvant aprotique, suivie d'une hydrolyse (cf. Sugasawa, T, et coll. J. Am. Chem. Soc. 100, p. 4842 (1978)). L'intermédiaire ainsi obtenu est ensuite traité par le chlorure d'éthylmalonyle dans un solvant aprotique tel que l'acétonitrile en présence d'une base telle que la triéthylamine, puis traité par un alcoolate alcalin, par exemple le méthylate de sodium dans le méthanol, pour donner le 7-chloro-4-chlorométhyl-6-méthyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate d'éthyle. Ce dernier est transformé en 2,7-dichloro-4-chlorométhyl-6-méthyl-3-quinolinecarboxylate d'éthyle par un traitement avec de l'oxychlorure de phosphoryle. On effectue ensuite une substitution nucléophile par traitement avec la 4-méthylpipéridine. La fonction carboxylate d'éthyle est ensuite réduite par l'hydrure de diisobutylaluminium dans un solvant aprotique tel que le dichlorométhane pour donner le composé de formule N2 . On peut éventuellement inverser l'ordre des deux dernières étapes.The compound of formula N 2 can be obtained according to the following process: the aniline of formula P 2 represented below
Figure 00090001
is ortho-acylated by reaction with chloroacetonitrile in the presence of boron trichloride and another Lewis acid such as aluminum trichloride, titanium tetrachloride or diethylaluminum chloride in an aprotic solvent or an aprotic solvent mixture , followed by hydrolysis ( see Sugasawa, T, et al. J. Am. Chem. Soc. 100 , p. 4842 (1978)). The intermediate thus obtained is then treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated with an alkaline alcoholate, for example sodium methylate in methanol , to give ethyl 7-chloro-4-chloromethyl-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate. The latter is transformed into ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate by treatment with phosphoryl oxychloride. Nucleophilic substitution is then carried out by treatment with 4-methylpiperidine. The ethyl carboxylate function is then reduced by diisobutylaluminum hydride in an aprotic solvent such as dichloromethane to give the compound of formula N 2 . You can optionally reverse the order of the last two steps.

Des analogues du composé intermédiaire du type de N2 ont été décrits dans la littérature et en particulier dans la demande PCT 95/05427.Analogs of the intermediate compound of the N 2 type have been described in the literature and in particular in PCT application 95/05427.

Le composé de formule (II) peut être transformé en sel pharmaceutiquement acceptable selon les méthodes usuelles. Des sels acceptables comprennent, à titre d'exemple et de façon non limitative, des sels d'addition d'acides inorganiques tels que chlorhydrate, sulfate, phosphate, diphosphate, bromhydrate et nitrate ou d'acides organiques tels que acétate, maléate, fumarate, tartrate, succinate, citrate, lactate, méthanesulfonate, p-toluènesulfonate, pamoate, salicylate, oxalate et stéarate. Pour d'autres exemples de sels pharmaceutiquement acceptables, on peut se référer à "Pharmaceutical Salts", J. Pharm. Sci. 66:1 (1977).The compound of formula ( II ) can be transformed into a pharmaceutically acceptable salt according to the usual methods. Acceptable salts include, by way of example and without limitation, addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acids such as acetate, maleate, fumarate , tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate. For other examples of pharmaceutically acceptable salts, reference may be made to "Pharmaceutical Salts", J. Pharm. Sci. 66: 1 (1977).

Les composés de la présente invention possèdent d'intéressantes propriétés pharmacologiques. C'est ainsi que les composés de la présente invention ont une activité inhibitrice de la topoisomérase I et II et une activité anti-tumorale. L'état de la technique suggère que les composés de l'invention présentent une activité anti-parasitaire et/ou anti-virale. Les composés de la présente invention peuvent ainsi être utilisés dans différentes applications thérapeutiques.The compounds of the present invention have interesting properties pharmacological. This is how the compounds of the present invention have an activity topoisomerase I and II inhibitor and anti-tumor activity. The state of technique suggests that the compounds of the invention exhibit anti-parasitic activity and / or anti-viral. The compounds of the present invention can thus be used in different therapeutic applications.

On trouvera ci-après, dans la partie expérimentale, une illustration des propriétés pharmacologiques des composés de l'invention.We will find below, in the experimental part, an illustration of the properties pharmacological of the compounds of the invention.

Les composés peuvent inhiber la topoisomérase, par exemple de type I et II, chez un patient, par exemple un mammifère tel que l'homme, par administration à ce patient d'une quantité thérapeutiquement efficace d'un composé de formule (I) ou de formule (II), ou d'un sel pharmaceutiquement acceptable d'un composé de formule (II), ou encore d'un mélange quelconque de ces derniers.The compounds can inhibit topoisomerase, for example of type I and II, in a patient, for example a mammal such as the man, by administration to this patient of a therapeutically effective quantity of a compound of formula ( I ) or of formula ( II ), or of a pharmaceutically acceptable salt of a compound of formula ( II ), or of any mixture thereof.

Les composés de l'invention possèdent une activité anti-tumorale. Ils peuvent être utilisés pour le traitement des tumeurs, par exemple des tumeurs exprimant une topoisomérase, chez un patient par administration audit patient d'une quantité thérapeutiquement efficace d'un composé de formule (II), ou d'un sel pharmaceutiquement acceptable d'un composé de formule (II), ou encore d'un mélange quelconque de ces derniers. Des exemples de tumeurs ou de cancers comprennent les cancers de l'oesophage, de l'estomac, des intestins, du rectum, de la cavité orale, du pharynx, du larynx, du poumon, du colon, du sein, du cervix uteri, du corpus endométrium, des ovaires, de la prostate, des testicules, de la vessie, des reins, du foie, du pancréas, des os, des tissus conjonctifs, de la peau, des yeux, du cerveau et du système nerveux central, ainsi que le cancer de la thyroïde, la leucémie, la maladie de Hodgkin, les lymphomes autres que ceux de Hodgkin, les myélomes multiples et autres.The compounds of the invention have anti-tumor activity. They can be used for the treatment of tumors, for example tumors expressing a topoisomerase, in a patient by administration to said patient of a therapeutically effective amount of a compound of formula ( II ), or of a pharmaceutically acceptable salt of a compound of formula ( II ), or of any mixture of the latter. Examples of tumors or cancers include cancers of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix uteri, endometrium corpus, ovaries, prostate, testes, bladder, kidneys, liver, pancreas, bones, connective tissue, skin, eyes, brain and central nervous system, as well than thyroid cancer, leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myelomas and others.

Ils peuvent également être utilisés pour le traitement des infections parasitiques par l'inhibition des hémoflagellates (par exemple dans la trypanosomie ou les infections leishmania) ou par inhibition de la plasmodie (comme par exemple dans la malaria), mais aussi le traitement des infections ou maladies virales.They can also be used for the treatment of parasitic infections by inhibition of hemoflagellates (for example in trypanosomy or infections leishmania) or by inhibition of the plasmodia (as for example in malaria), but also the treatment of viral infections or diseases.

Ces propriétés rendent le produit de formule (II) apte à une utilisation pharmaceutique. La présente demande a également pour objet, à titre de médicaments, le produit de formule (II) telles que définies ci-dessus, ou les sels d'addition avec les acides minéraux ou organiques pharmaceutiquement acceptables du produit de formule (II) tel que par exemple le sel de formule (III) précédemment décrit, ou encore un mélange quelconque de ces derniers. L'invention concerne de même les compositions pharmaceutiques contenant, à titre de principe actif, l'un au moins des médicaments tels que définis ci-dessus. These properties make the product of formula ( II ) suitable for pharmaceutical use. The present application also relates, as medicaments, to the product of formula ( II ) as defined above, or to the addition salts with pharmaceutically acceptable inorganic or organic acids of the product of formula ( II ) such as for example the salt of formula ( III ) previously described, or alternatively any mixture of the latter. The invention likewise relates to pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.

L'invention concerne ainsi des compositions pharmaceutiques contenant un composé de l'invention ou un sel additif d'acide pharmaceutiquement acceptable de celui-ci, en association avec un support pharmaceutiquement acceptable suivant le mode d'administration choisie (par exemple orale, intraveineuse, intrapéritonéales, intramusculaires, trans-dermique ou sous-cutanée). La composition pharmaceutique (par exemple thérapeutique) peut être sous forme solide, liquide, de liposomes ou de micelles lipidiques.The invention thus relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid additive salt thereof, in association with a pharmaceutically acceptable carrier according to the mode chosen administration (e.g. oral, intravenous, intraperitoneal, intramuscular, trans-dermal or subcutaneous). The pharmaceutical composition (by therapeutic example) can be in solid, liquid, liposome or micelle form lipid.

La composition pharmaceutique peut être sous forme solide comme, par exemple, les poudres, pilules, granules, comprimés, liposomes, gélules ou suppositoires. La pilule, le comprimé ou la gélule peuvent être revêtus d'une substance capable de protéger la composition de l'action de l'acide gastrique ou des enzymes dans l'estomac du sujet pendant une période de temps suffisante pour permettre à cette composition de passer non digérée dans l'intestin grêle de ce dernier. Le composé peut aussi être administré localement, par exemple à l'emplacement même de la tumeur. Le composé peut aussi être administré selon le processus de la libération prolongée (par exemple une composition à libération prolongée ou une pompe d'infusion). Les supports solides appropriés peuvent être, par exemple, le phosphate de calcium, le stéarate de magnésium, le carbonate de magnésium, le talc, les sucres, le lactose, la dextrine, l'amidon, la gélatine, la cellulose, la cellulose de méthyle, la cellulose carboxyméthyle de sodium, la polyvinylpyrrolidine et la cire. Les compositions pharmaceutiques contenant un composé de l'invention peuvent donc également se présenter sous forme liquide comme, par exemple, des solutions, des émulsions, des suspensions ou une formulation à libération prolongée. Les supports liquides appropriés peuvent être, par exemple, l'eau, les solvants organiques tels que le glycérol ou les glycols tel que le polyéthylène glycol, de même que leurs mélanges, dans des proportions variées, dans l'eau.The pharmaceutical composition can be in solid form such as, for example, powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, the tablet or capsule may be coated with a substance capable of protecting the composition of the action of stomach acid or enzymes in the stomach of the subject for a period of time sufficient to allow this composition to pass non digested in the small intestine of the latter. The compound can also be administered locally, for example at the site of the tumor. The compound can also be administered using the extended release process (e.g. extended release or infusion pump). The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, carbonate magnesium, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound of the invention can therefore also be in liquid form such as, for example, solutions, emulsions, suspensions or extended release formulation. Media suitable liquids can be, for example, water, organic solvents such as glycerol or glycols such as polyethylene glycol, as well as their mixtures, in various proportions, in water.

L'invention a également pour objet l'utilisation du produit de formule (II) telle que définies ci-dessus, ou des sels d'addition avec les acides minéraux ou organiques pharmaceutiquement acceptables du produit de formule (II), tel que par exemple le sel de formule (III) précédemment décrit, ou encore d'un mélange de ces derniers, pour la préparation de médicaments destinés à inhiber les topoisomérases, et plus particulièrement les topoisomérases de type I ou de type II, de médicaments destinés à traiter les tumeurs, de médicaments destinés à traiter les infections parasitaires, ainsi que de médicaments destinés traiter des infections ou maladies virales.A subject of the invention is also the use of the product of formula (II) as defined above, or of the addition salts with pharmaceutically acceptable mineral or organic acids of the product of formula (II) , such as for example the salt of formula (III) previously described, or a mixture of the latter, for the preparation of medicaments intended to inhibit topoisomerases, and more particularly topoisomerases type I or type II, of medicaments intended to treat tumors, drugs to treat parasitic infections, and drugs to treat viral infections or diseases.

La dose d'un composé selon la présente invention, à prévoir pour le traitement des maladies ou troubles mentionnés ci-dessus, varie suivant le mode d'administration, l'âge et le poids corporel du sujet à traiter ainsi que l'état de ce dernier, et il en sera décidé en définitive par le médecin ou le vétérinaire traitant. Une telle quantité déterminée par le médecin ou le vétérinaire traitant est appelée ici "quantité thérapeutiquement efficace".The dose of a compound according to the present invention, to be provided for the treatment of diseases or disorders mentioned above, varies according to the mode of administration, age and the body weight of the subject to be treated as well as the state of the latter, and it will be decided in final by the attending physician or veterinarian. Such an amount determined by the the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".

A moins qu'ils ne soient définis d'une autre manière, tous les termes techniques et scientifiques utilisés ici ont la même signification que celle couramment comprise par un spécialiste ordinaire du domaine auquel appartient cette invention. De même, toutes les publications, demandes de brevets, tous les brevets et toutes autres références mentionnés ici sont incorporés par référence.Unless otherwise defined, all technical terms and scientists used here have the same meaning as that commonly understood by a ordinary specialist in the field to which this invention belongs. Likewise, all publications, patent applications, all patents and all other references mentioned here are incorporated by reference.

Les exemples suivants sont présentés pour illustrer les procédures ci-dessus et ne doivent en aucun cas être considérés comme une limite à la portée de l'invention.The following examples are presented to illustrate the above procedures and should not be in no case be considered as a limit to the scope of the invention.

PARTIE EXPÉRIMENTALE : EXPERIMENTAL PART : Exemple 1 : (+)-5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino[3,4-c]pyridin-3,9-dione [(+)-EHHOPD] Example 1 : ( + ) -5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino [3,4-c] pyridin-3,9-dione [( + ) -EHHOPD] 1.a. Sel de quinidine de l'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque :1.a. Quinidine salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic acid :

Du 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoate de tertiobutyle (40 g ; 100 mmol) est traité par de l'acide trifluoroacétique (150 ml) et le milieu réactionnel est agité pendant 18 h à 20 °C. Après évaporation de l'acide trifluoroacétique, du chlorure de méthylène (200 ml) est coulé et une solution saturée en bicarbonate de sodium est introduite jusqu'à pH = 7,5-8. Après décantation, la phase aqueuse est lavée avec 100 ml de chlorure de méthylène. Le pH de la phase aqueuse est alors ramené à 1 par ajout d'une solution d'acide chlorhydrique 6 N. Le produit est ensuite extrait de la phase aqueuse par du chlorure de méthylène (2 fois 200 ml). La solution est séchée sur du sulfate de magnésium et concentrée. L'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque (31,1 g ; 90 mmol) ainsi obtenu, repris dans de l'alcool isopropylique (30 ml), est traité par une solution de quinidine (29,2 g ; 90 mmol) dans de l'alcool isopropylique (30 ml) à 50 °C sous agitation jusqu'à dissolution complète. On laisse alors la température redescendre jusqu'à 40 °C, l'agitation est arrêtée et on laisse évoluer la température jusqu'à 20 °C. Le milieu est amené à 0 °C sans agitation puis maintenu à cette température pendant 16 heures. On laisse ensuite la température remonter jusqu'à 20 °C et on agite jusqu'à cristallisation. Le milieu est dilué par de l'alcool isopropylique puis filtré. Le précipité est rincé par de l'alcool isopropylique. Le sel de l'énantiomère (+) précipite (m=26.6 g) alors que le sel de l'énantiomère (-) reste en solution dans l'alcool isopropylique. On recueille donc le filtrat qui est concentré pour donner une huile (34 g) qui est engagée sans autre purification dans l'étape suivante.Tertiary butyl 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoate (40 g; 100 mmol) is treated with trifluoroacetic acid (150 ml) and the medium The reaction mixture is stirred for 18 h at 20 ° C. After evaporation of the trifluoroacetic acid, methylene chloride (200 ml) is poured in and a saturated bicarbonate solution sodium is introduced until pH = 7.5-8. After decantation, the aqueous phase is washed with 100 ml of methylene chloride. The pH of the aqueous phase is then reduced to 1 by adding a 6N hydrochloric acid solution. The product is then extracted from the aqueous phase with methylene chloride (2 times 200 ml). The solution is dried on magnesium sulfate and concentrated. 3- (3-Benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic acid (31.1 g; 90 mmol) thus obtained, taken up in alcohol isopropyl (30 ml), is treated with a solution of quinidine (29.2 g; 90 mmol) in isopropyl alcohol (30 ml) at 50 ° C with stirring until complete dissolution. We then let the temperature drop to 40 ° C, the stirring is stopped and the mixture is left change the temperature to 20 ° C. The medium is brought to 0 ° C. without stirring then maintained at this temperature for 16 hours. Then let the temperature rise up to 20 ° C and stirred until crystallization. The medium is diluted with alcohol isopropyl then filtered. The precipitate is rinsed with isopropyl alcohol. Salt the (+) enantiomer precipitates (m = 26.6 g) while the (-) enantiomer salt remains in solution in isopropyl alcohol. We therefore collect the filtrate which is concentrated to give an oil (34 g) which is used without further purification in the next step.

Les produits sont analysés par HPLC sur colonne CHIRAL AGP 5µ (10 cm x 4mm) éluée par un mélange alcool isopropylique/eau/tampon phosphate, pH = 6,5 : 30/920/50, à un débit de 1,2 ml/min, détection UV à 280 nm. Les temps de rétention obtenus sont 6,4 minutes pour l'énantiomère (-) et 2,8 minutes pour l'énantiomère (+). Le rapport énantiomère (-) / énantiomère (+) est de 83 / 17.The products are analyzed by HPLC on a CHIRAL AGP 5µ column (10 cm x 4mm) eluted with an isopropyl alcohol / water / phosphate buffer mixture, pH = 6.5: 30/920/50, at a flow rate of 1.2 ml / min, UV detection at 280 nm. The retention times obtained are 6.4 minutes for the (-) enantiomer and 2.8 minutes for the (+) enantiomer. The report enantiomer (-) / enantiomer (+) is 83/17.

1.b. Acide (-)-3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxypentanoïque1.b. (-) - 3- (3-Benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid

La solution dans l'alcool isopropylique du sel de quinidine de l'énantiomère (-) de l'acide 3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque (étape 1.a) est concentrée. Le concentrat est repris dans 270 ml de chlorure de méthylène et 270 ml d'une solution d'acide chlorhydrique 1N. Le milieu réactionnel est agité pendant 16 heures à 20°C. Après décantation, la phase organique est concentrée, le concentrat est repris dans le méthanol pour être engagé dans la phase suivante.The solution in isopropyl alcohol of the quinidine salt of the (-) enantiomer of the acid 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic (step 1.a) is concentrated. The concentrate is taken up in 270 ml of methylene chloride and 270 ml of a 1N hydrochloric acid solution. The reaction medium is stirred for 16 hours at 20 ° C. After decantation, the organic phase is concentrated, the concentrate is taken up in methanol to be used in the next phase.

On obtient 13,5 g de produit (rendement de 87%) et une proportion énantiomère (-) /énantiomère (+) de 85 / 15.13.5 g of product are obtained (87% yield) and an enantiomer (-) / enantiomer proportion (+) of 85/15.

Les temps de rétention HPLC (même protocole qu'en 1.a.) sont :

  • énantiomère (-) : 6,4 minutes
  • énantiomère (+) : 2,8 minutes
The HPLC retention times (same protocol as in 1.a.) are:
  • enantiomer (-): 6.4 minutes
  • enantiomer (+): 2.8 minutes

1.c. (+)-5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino[3,4-c] pyridin-3,9-dione :1 C. (+) - 5-Ethyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino [3,4-c] pyridin-3,9-dione:

L'acide (-)-3-(3-benzyloxyméthyl-2-méthoxy-4-pyridyl)-3-hydroxy-pentanoïque (13,5 g ; 39 mmol ; étape 1.b) est mis en solution dans 87 ml de méthanol. Cette solution est coulée sous azote sur du Palladium 10% sur charbon humide à 50% (27,7 g ; 13 mmol). Le milieu réactionnel est agité pendant 5 minutes, puis est coulée une solution de formiate d'ammonium (11,5 g ; 183 mmol) dans 135 ml de méthanol. Le milieu réactionnel est agité pendant 30 minutes en laissant la température évoluer, puis il est chauffé à 40°C pendant 30 minutes. Le milieu est alors filtré sur lit de Clarcel et est concentré. On coule 40 ml de toluène que l'on évapore ; cette opération est répétée afin d'éliminer le méthanol. Le résidu ainsi obtenu est repris dans 45 ml de THF. On coule ensuite une solution de dicyclohexylcarbodiimide (7,180 g ; 34,5 mmol) dans 20 ml de THF. Le milieu réactionnel est chauffé à 50°C pendant 1 heure. Le mélange est ramené à 20°C puis la dicyclohexylurée est filtrée. Le filtrat est concentré à sec. Le résidu est mis en solution dans 46 ml d'acétonitrile, on lui ajoute 6,0 g (40,5 mmol.) d'iodure de sodium puis 5,13 ml (40,5 mmol) de chlorure de triméthylsilyle. Le milieu réactionnel est maintenu sous agitation à température ambiante pendant 5 heures. On introduit alors 28 ml d'acétonitrile et 5,6 ml d'eau. Le précipité obtenu est filtré puis repris dans 1 ml d'eau, et le pH est ramené à 7,5 par ajout d'une solution d'ammoniaque. Le solide obtenu est filtré et séché. On obtient m = 4,2 g de produit final avec un rendement de 34 % et une proportion énantiomère (+) / énantiomère (-) de 88,4/11,6.(-) - 3- (3-Benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxy-pentanoic acid (13.5 g; 39 mmol; step 1.b) is dissolved in 87 ml of methanol. This solution is poured under nitrogen onto 10% Palladium on 50% wet charcoal (27.7 g; 13 mmol). The reaction medium is stirred for 5 minutes, then is poured a solution of ammonium formate (11.5 g; 183 mmol) in 135 ml of methanol. The reaction medium is stirred for 30 minutes while allowing the temperature to change, then it is heated at 40 ° C for 30 minutes. The medium is then filtered on a Clarcel bed and is concentrated. 40 ml of toluene are poured in and evaporated; this operation is repeated so to remove methanol. The residue thus obtained is taken up in 45 ml of THF. We sink then a solution of dicyclohexylcarbodiimide (7,180 g; 34.5 mmol) in 20 ml of THF. The reaction medium is heated at 50 ° C for 1 hour. The mixture is brought to 20 ° C then the dicyclohexylurea is filtered. The filtrate is concentrated to dryness. The residue is put dissolved in 46 ml of acetonitrile, 6.0 g (40.5 mmol.) of iodide sodium then 5.13 ml (40.5 mmol) of trimethylsilyl chloride. The reaction medium is kept stirring at room temperature for 5 hours. We then introduce 28 ml of acetonitrile and 5.6 ml of water. The precipitate obtained is filtered and then taken up in 1 ml of water, and the pH is reduced to 7.5 by adding an ammonia solution. The solid obtained is filtered and dried. We obtain m = 4.2 g of final product with a yield of 34% and a enantiomer (+) / enantiomer (-) proportion of 88.4 / 11.6.

L'analyse HPLC est réalisée sur une colonne Chiralcel OD 25 cm x 4,6 mm, les éluants utilisés sont l'heptane 600 et l'éthanol 400 et le débit est de 1 ml/min 210 nm. Les temps de rétention obtenus sont :

  • énantiomère (-) : 7,1 minutes
  • énantiomère (+) : 9 minutes.
The HPLC analysis is carried out on a Chiralcel OD column 25 cm x 4.6 mm, the eluents used are heptane 600 and ethanol 400 and the flow rate is 1 ml / min 210 nm. The retention times obtained are:
  • enantiomer (-): 7.1 minutes
  • enantiomer (+): 9 minutes.

Le produit est repris dans l'acétone (40 ml), puis on ajoute de l'eau (150 ml). On laisse précipiter et on obtient 3 g de produit avec une proportion énantiomère (+) /énantiomère (-) de 99,4 / 0,6.
RMN 1H (250 MHz, DMSO D6): 0,8 (t, 3H, CH3 -CH2); 1,65 (m, 2H, CH2 -CH3); 3,00-3,35 (q, 1H+1H, -CH2-C=O); 5,3 (q, 2H, CH2-O); 5,7 (s, -OH); 6,35 (d, 1H aromatique); 7,3 (d, 1H aromatique); 11,7 (s, N-H). The product is taken up in acetone (40 ml), then water (150 ml) is added. It is left to precipitate and 3 g of product are obtained with an enantiomer (+) / enantiomer (-) proportion of 99.4 / 0.6.
1 H NMR (250 MHz, DMSO D6): 0.8 ( t , 3H, CH 3 -CH 2 ); 1.65 ( m, 2H, CH 2 -CH 3 ); 3.00-3.35 ( q , 1H + 1H, -CH 2 -C = O); 5.3 ( q , 2H, CH 2 -O); 5.7 ( s , -OH); 6.35 ( d, 1H aromatic); 7.3 ( d, 1H aromatic); 11.7 (s, NH).

Exemple 2 : (+)-chlorure de 1-[9-chloro-5-éthyl-5-hydroxy-10-méthyl-3,15-dioxo-4,5,13,15-tétrahydro-1H,3H-oxépino[3',4':6,7]indolizino[1,2-b]quinolin-12-ylméthyl]-4-méthyl-hexahydropyridinium Example 2 : ( + ) -chloride of 1- [9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H, 3H-oxepino [ 3 ', 4': 6,7] indolizino [1,2-b] quinolin-12-ylmethyl] -4-methyl-hexahydropyridinium 2.a. 1-(2-amino-4-chloro-5-méthylphényl)-2-chloro-éthanone :2.a. 1- (2-amino-4-chloro-5-methylphenyl) -2-chloro-ethanone:

De la 3-chloro-4-méthylaniline (44,4 ml; 0,366 mol) dans du 1,2-dichloroéthane (440 ml), sous atmosphère d'argon, est refroidi par un bain de glace. On ajoute goutte à goutte et dans l'ordre à ce mélange : du trichlorure de bore (1M dans l'heptane; 400 ml; 0,4 mol), du chloroacétonitrile (28 ml; 0,44 mol) et du chlorure de diéthylaluminium (1M dans l'heptane; 400 ml; 0,4 mol). Durant l'addition, la température est maintenue en dessous de 20 °C. Le mélange résultant est ensuite chauffé à reflux durant 3 h, puis refroidi à 10 °C. On procède alors avec précaution à l'hydrolyse du milieu réactionnel au moyen d'acide chlorhydrique 2N (240 ml) et on chauffe à reflux durant 1 h. On ajoute de l'eau (1 l) et de l'acétate d'éthyle (1 l), on agite le mélange obtenu durant 15 mn avant de séparer les phases. La phase aqueuse est à nouveau extraite avec de l'acétate d'éthyle (200 ml), et on lave avec de l'eau (500 ml) les phases organiques combinées. On sèche sur sulfate de magnésium et on concentre la phase organique. Le résidu est repris dans de l'éther de pétrole (fraction ayant un point d'ébullition de 45 à 60 °C; 150 ml) et le mélange ainsi obtenu est laissé reposer durant 16 h à 4 °C. Le précipité résultant est récupéré par filtration, lavé avec de l'éther de pétrole et séché sous pression réduite pour donner le produit du titre (25 g ; 31 % de rendement). Pf 129-130 °C.
RMN 1H (DMSO) : 2,20 (s, 3H); 4.98 (s, 2H); 6,90 (s, 1H); 7,15 (pic large, 2H); 7,70 (s, 1H).
IR (KBr) : 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm-1.3-chloro-4-methylaniline (44.4 ml; 0.366 mol) in 1,2-dichloroethane (440 ml), under an argon atmosphere, is cooled by an ice bath. To this mixture are added dropwise and in order: boron trichloride (1M in heptane; 400 ml; 0.4 mol), chloroacetonitrile (28 ml; 0.44 mol) and diethylaluminum chloride (1M in heptane; 400 ml; 0.4 mol). During the addition, the temperature is kept below 20 ° C. The resulting mixture is then heated at reflux for 3 h, then cooled to 10 ° C. The reaction medium is then carefully hydrolyzed using 2N hydrochloric acid (240 ml) and the mixture is heated at reflux for 1 h. Water (1 l) and ethyl acetate (1 l) are added, the mixture obtained is stirred for 15 min before separating the phases. The aqueous phase is again extracted with ethyl acetate (200 ml), and the combined organic phases are washed with water (500 ml). It is dried over magnesium sulfate and the organic phase is concentrated. The residue is taken up in petroleum ether (fraction having a boiling point of 45 to 60 ° C; 150 ml) and the mixture thus obtained is left to stand for 16 h at 4 ° C. The resulting precipitate is recovered by filtration, washed with petroleum ether and dried under reduced pressure to give the title product (25 g; 31% yield). P f 129-130 ° C.
1 H NMR (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15 (broad peak, 2H); 7.70 (s, 1H).
IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm -1 .

2.b. 7-chloro-4-chlorométhyl-6-méthyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate d'éthyle :2.b. 7-chloro-4-chloromethyl-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate ethyl:

Du produit de l'étape 3.a (25 g; 0,11 mol) et de la triéthylamine (30,6 ml; 0,22 mol) sont mélangés dans de l'acétonitrile (520 ml). Du chlorure d'éthylmalonyle (28,1 ml; 0,22 mol) est ajouté à température ambiante et sous atmosphère d'argon. Le mélange obtenu est agité durant 3 h. De l'éthanolate de sodium (préparé par dissolution de 3 g, soit 0,13 mol, de sodium dans 140 ml d'éthanol absolu) est ensuite ajouté goutte à goutte et le mélange résultant est agité à température ambiante durant 16 h. Le précipité est récupéré par filtration, lavé successivement par de l'éthanol, de l'eau, de l'éthanol et de l'éther. Il est ensuite séché sous pression réduite à 70 °C sur du pentoxide de phosphore pour donner le produit du titre (28,6 g; 83 % de rendement) sous forme d'une poudre blanchâtre.
RMN 1H (DMSO) : 1,30 (t, 3H); 2,40 (s, 3H); 4,35 (q, 2H); 4,85 (s, 2H); 7,41 (s, 1H); 7,91 (s, 1H); 12,15 (pic large, 1H).
IR (KBr) : 879, 1108, 1250, 1288, 1483, 1664, 1721 cm-1.Product from step 3.a (25 g; 0.11 mol) and triethylamine (30.6 ml; 0.22 mol) are mixed in acetonitrile (520 ml). Ethylmalonyl chloride (28.1 ml; 0.22 mol) is added at room temperature and under an argon atmosphere. The mixture obtained is stirred for 3 h. Sodium ethanolate (prepared by dissolving 3 g, ie 0.13 mol, of sodium in 140 ml of absolute ethanol) is then added dropwise and the resulting mixture is stirred at room temperature for 16 h. The precipitate is recovered by filtration, washed successively with ethanol, water, ethanol and ether. It is then dried under reduced pressure at 70 ° C on phosphorus pentoxide to give the title product (28.6 g; 83% yield) in the form of a whitish powder.
1 H NMR (DMSO): 1.30 (t, 3H); 2.40 (s, 3H); 4.35 (q, 2H); 4.85 (s, 2H); 7.41 (s, 1H); 7.91 (s, 1H); 12.15 (broad peak, 1H).
IR (KBr): 879, 1108, 1250, 1288, 1483, 1664, 1721 cm -1 .

2.c. 2,7-dichloro-4-chlorométhyl-6-méthyl-3-quinolinecarboxylate d'éthyle :2.c. 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate ethyl:

Du produit de l'étape 3.b (28,4 g; 90 mmol) est chauffé durant 4 h à reflux dans de l'oxychlorure de phosphore (400 ml). Le mélange obtenu est concentré sous pression réduite (20 mm Hg) à 80 °C. Le résidu est repris dans du diisopropyléther (400 ml). Le précipité résultant est récupéré par filtration, lavé avec de l'éther et de l'éther de pétrole, puis séché sous pression réduite pour donner le produit du titre (25,4 g; 85 % de rendement) sous forme d'une poudre blanchâtre (Pf 126-127 °C).
RMN 1H (DMSO): 1,37 (t, 3H); 2,58 (s, 3H); 4,49 (q, 2H); 5,14 (s, 2H); 8,16 (s, 1H); 8,35 (s, 1H).
IR (KBr) : 874, 1006, 1163, 1243, 1278, 1577, 1723 cm-1.Product from step 3.b (28.4 g; 90 mmol) is heated for 4 h at reflux in phosphorus oxychloride (400 ml). The mixture obtained is concentrated under reduced pressure (20 mm Hg) at 80 ° C. The residue is taken up in diisopropyl ether (400 ml). The resulting precipitate is recovered by filtration, washed with ether and petroleum ether, then dried under reduced pressure to give the title product (25.4 g; 85% yield) in the form of a powder whitish (P f 126-127 ° C).
1 H NMR (DMSO): 1.37 (t, 3H); 2.58 (s, 3H); 4.49 (q, 2H); 5.14 (s, 2H); 8.16 (s, 1H); 8.35 (s, 1H).
IR (KBr): 874, 1006, 1163, 1243, 1278, 1577, 1723 cm -1 .

2.d. 2,7-dichloro-4-chlorométhyl-6-méthyl-3-quinolylméthanol :2.d 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolylmethanol:

Du produit de l'étape 3.c (25,2 g; 76,5 mmol) est mélangé sous atmosphère d'argon à du dichloroéthane (630 ml). De l'hydrure de diisobutylaluminium (1M dans du dichlorométhane; 307 ml; 307 mmol) est ajouté goutte à goutte tandis que le mélange réactionnel est agité et la température maintenue en dessous de 20 °C. Le mélange réactionnel est ensuite agité à température ambiante pendant 3 heures, puis versé dans une solution aqueuse de tartrate de potassium (concentrée à 20 % en poids; 1,5 l). L'émulsion ainsi obtenue est agitée vigoureusement durant 1 h, filtrée sur célite et les deux phases sont alors séparées. La phase aqueuse est extraite par de l'acétate d'éthyle (200 ml) et les phases organiques combinées sont lavées avec une solution aqueuse de chlorure de sodium (concentrée à 20 % en poids; 500 ml). La phase organique obtenue est séchée sur sulfate de magnésium, filtrée et concentrée sous pression réduite. Le résidu est repris dans du diéthyléther (50 ml) et le précipité résultant est récupéré par filtration. Par séchage sous pression réduite, on obtient le produit du titre (18,3 g; 93 % de rendement) sous forme d'une poudre blanchâtre (Pf 169-170 °C).
RMN 1H (DMSO): 2,57 (t, 3H); 4,84 (s, 2H); 5,36 (s, 2H); 8,06 (s, 1H); 8,27 (s, 1H).
IR (KBr): 870, 1022, 1102, 1304, 1482, 1567 cm-1.Product from step 3.c (25.2 g; 76.5 mmol) is mixed under an argon atmosphere with dichloroethane (630 ml). Diisobutylaluminum hydride (1M in dichloromethane; 307 ml; 307 mmol) is added dropwise while the reaction mixture is stirred and the temperature maintained below 20 ° C. The reaction mixture is then stirred at room temperature for 3 hours, then poured into an aqueous solution of potassium tartrate (concentrated to 20% by weight; 1.5 l). The emulsion thus obtained is vigorously stirred for 1 h, filtered through celite and the two phases are then separated. The aqueous phase is extracted with ethyl acetate (200 ml) and the combined organic phases are washed with an aqueous solution of sodium chloride (concentrated to 20% by weight; 500 ml). The organic phase obtained is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether (50 ml) and the resulting precipitate is recovered by filtration. By drying under reduced pressure, the title product is obtained (18.3 g; 93% yield) as a white powder (P f 169-170 ° C).
1 H NMR (DMSO): 2.57 (t, 3H); 4.84 (s, 2H); 5.36 (s, 2H); 8.06 (s, 1H); 8.27 (s, 1H).
IR (KBr): 870, 1022, 1102, 1304, 1482, 1567 cm -1 .

2.e. 2,7-dichloro-6-méthyl-4-(4-méthylpipéridinométhyl)-3-quinolylméthanol :2.e. 2,7-dichloro-6-methyl-4- (4-méthylpipéridinométhyl) -3-quinolylméthanol :

Une solution de produit de l'étape 3.d (16,2 g; 55,7 mmol) dans du THF (70 ml) est traitée par une solution de 4-méthylpipéridine (23 ml; 195 mmol). Le mélange obtenu est agité à température ambiante durant 2 h. On ajoute de l'eau (200 ml) et du dichloroéthane (200 ml). La phase organique est lavée avec une solution aqueuse de chlorure de sodium (concentrée à 20 % en poids; 100 ml), séchée sur du sulfate de magnésium et concentrée sous pression réduite. Par cristallisation du résidu dans du diéthyléther, on obtient le produit du titre (18,3 g; 93 % de rendement) sous forme d'un solide cristallin blanc (Pf 170-171,5 °C).
RMN 1H (CDCl3) : 0,88 (d, 3H); 1,17 (m, 2H); 1,42 (m, 1H); 1,60 (m, 2H); 2,19 (t, 2H); 2,56 (s, 3H); 2,82 (d, 2H); 4,02 (s, 2H); 4,93 (s, 2H); 6,36 (pic large, 1H); 7,95 (s, 1H); 8,02 (s, 1H).
IR (KBr) : 971, 1013, 1105, 1293, 1479, 1559 cm-1. A solution of product from step 3.d (16.2 g; 55.7 mmol) in THF (70 ml) is treated with a solution of 4-methylpiperidine (23 ml; 195 mmol). The mixture obtained is stirred at room temperature for 2 h. Water (200 ml) and dichloroethane (200 ml) are added. The organic phase is washed with an aqueous solution of sodium chloride (concentrated to 20% by weight; 100 ml), dried over magnesium sulfate and concentrated under reduced pressure. Crystallization of the residue from diethyl ether, the title product is obtained (18.3 g; 93% yield) as a white crystalline solid (P f 170 to 171.5 ° C).
1 H NMR (CDCl 3 ): 0.88 (d, 3H); 1.17 (m, 2H); 1.42 (m, 1H); 1.60 (m, 2H); 2.19 (t, 2H); 2.56 (s, 3H); 2.82 (d, 2H); 4.02 (s, 2H); 4.93 (s, 2H); 6.36 (broad peak, 1H); 7.95 (s, 1H); 8.02 (s, 1H).
IR (KBr): 971, 1013, 1105, 1293, 1479, 1559 cm -1 .

2.f. (+)-8-[2,7-dichloro-6-méthyl-4-(4-méthylpipéridinométhyl)-3-quinolylméthyl]-5-éthyl-5-hydroxy-1,3,4,5,8,9-hexahydrooxépino[3,4-c]pydidine-3,9-dione :2 F. (+) - 8- [2,7-dichloro-6-methyl-4- (4-méthylpipéridinométhyl) -3-quinolylmethyl] -5-ethyl-5-hydroxy-1,3,4,5,8,9- hexahydrooxépino [3,4-c] pydidine-3,9-dione :

Une suspension de (+)-EHHOPD (obtenue à l'étape 1.c.; 1,56 g; 7,0 mmol) dans du dioxane anhydre (70 ml) est traitée successivement, sous atmosphère d'argon, par du produit de l'étape 3.e (2,47 g; 7,0 mmol), de la triphénylphosphine (2,02 g; 7,7 mmol) et du diisopropyl azodicarboxylate (1,07 ml; 10,5 mmol). Le mélange est agité à température ambiante durant 16 h. Les substances volatiles sont ensuite évaporées sous pression réduite. Le résidu est purifié par chromatographie sur colonne de silice (éluant : acétate d'éthyle). Le solide obtenu est repris dans du diéthyléther, filtré et séché pour donner le produit du titre (1,96 g: 50 % de rendement) sous forme d'un solide blanchâtre (Pf 182 °C).
RMN 1H (DMSO): 0,89 (m, 8H); 1,23 (m, 1H); 1,41 (t, 2H); 1,64 (m, 2H); 2,09 (q, 2H); 2,59 (m, 5H); 3,15 (dd, 2H); 4,06 (dd, 2H); 5,31 (dd, 2H); 5,35 (dd, 2H); 5,75 (s, 1H); 6,29 (d, 1H); 7,17 (d, 1H); 8,06 (s, 1H); 8,46 (s, 1H).
IR (KBr): 878, 1053, 1275, 1474, 1572, 1648, 1747 cm-1.A suspension of (+) - EHHOPD (obtained in step 1.c .; 1.56 g; 7.0 mmol) in anhydrous dioxane (70 ml) is treated successively, under an argon atmosphere, with product from step 3.e (2.47 g; 7.0 mmol), triphenylphosphine (2.02 g; 7.7 mmol) and diisopropyl azodicarboxylate (1.07 ml; 10.5 mmol). The mixture is stirred at room temperature for 16 h. The volatile substances are then evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate). The solid obtained is taken up in diethyl ether, filtered and dried to give the title product (1.96 g: 50% yield) in the form of a whitish solid ( mp 182 ° C).
1 H NMR (DMSO): 0.89 (m, 8H); 1.23 (m, 1H); 1.41 (t, 2H); 1.64 (m, 2H); 2.09 (q, 2H); 2.59 (m, 5H); 3.15 (dd, 2H); 4.06 (dd, 2H); 5.31 (dd, 2H); 5.35 (dd, 2H); 5.75 (s, 1H); 6.29 (d, 1H); 7.17 (d, 1H); 8.06 (s, 1H); 8.46 (s, 1H).
IR (KBr): 878, 1053, 1275, 1474, 1572, 1648, 1747 cm -1 .

2.g. (+)-9-chloro-5-éthyl-5-hydroxy-10-méthyl-12-(4-méthylpipéridinométhyl)-4,5,13,15-tétrahydro-1H,3H-oxépino[3',4';6,7]indolizino[1,2-c]quinoline-3,15-dione :2.g. (+) - 9-chloro-5-ethyl-5-hydroxy-10-methyl-12- (4-méthylpipéridinométhyl) -4,5,13,15-tetrahydro-1H, 3H-oxepino [3 ', 4'; 6,7] indolizino [1,2-c] quinoline-3,15-dione :

Un mélange de produit de l'étape 3.f (3,80 g; 6,80 mmol), de bromure de tétrabutylammonium (2,42 g; 7,5 mmol), d'acétate de potassium (1,00 g; 10,2 mmol), de triphénylphosphine (890 mg; 3,4 mmol) et d'acétate de palladium (II) (220 mg; 0,68 mmol) est agité sous atmosphère d'argon dans de l'acétonitrile anhydre (85 mg) à reflux durant 24 h. Après refroidissement à température ambiante, le précipité résultant est récupéré par filtration et lavé successivement par de l'acétonitrile, de l'eau, de l'acétone et du diéthyléther pour donner, après séchage sous pression réduite, le produit du titre (2,5 g; 70 % de rendement) sous forme d'une poudre blanchâtre.
RMN 1H (DMSO) : 0,86 (m, 6H); 1,12 (q, 2H); 1,36 (m, 1H); 1,56 (d, 2H); 1,84 (q, 2H); 2,12 (t, 2H); 2,56 (s, 3H); 2,83 (dd, 2H); 3,26 (dd, 2H); 4,03 (dd, 2H); 5,28 (dd, 2H); 5,45 (dd, 2H); 6,04 (s, 1H); 7,34 (s, 1H); 8,14 (s, 1H); 8,38 (s, 1H).
IR (KBr) : 870, 1058, 1208, 1280, 1477, 1593, 1655, 1749 cm-1. A mixture of product from step 3.f (3.80 g; 6.80 mmol), tetrabutylammonium bromide (2.42 g; 7.5 mmol), potassium acetate (1.00 g; 10.2 mmol), triphenylphosphine (890 mg; 3.4 mmol) and palladium (II) acetate (220 mg; 0.68 mmol) is stirred under an argon atmosphere in anhydrous acetonitrile (85 mg) at reflux for 24 h. After cooling to room temperature, the resulting precipitate is recovered by filtration and washed successively with acetonitrile, water, acetone and diethyl ether to give, after drying under reduced pressure, the title product (2, 5 g; 70% yield) in the form of a whitish powder.
1 H NMR (DMSO): 0.86 (m, 6H); 1.12 (q, 2H); 1.36 (m, 1H); 1.56 (d, 2H); 1.84 (q, 2H); 2.12 (t, 2H); 2.56 (s, 3H); 2.83 (dd, 2H); 3.26 (dd, 2H); 4.03 (dd, 2H); 5.28 (dd, 2H); 5.45 (dd, 2H); 6.04 (s, 1H); 7.34 (s, 1H); 8.14 (s, 1H); 8.38 (s, 1H).
IR (KBr): 870, 1058, 1208, 1280, 1477, 1593, 1655, 1749 cm -1 .

2.h. (+)-chlorure de 1-[(5R)-9-chloro-5-éthyl-5-hydroxy-10-méthyl-3,15-dioxo-4,5,13,15-tétrahydro-1H,3H-oxépino[3',4':6,7]indolizino[1,2-c]quinolin-12-ylméthyl]-4-méthyl-hexahydropyridinium :2.h. (+) - 1 - [(5R) -9-chloro-5-ethyl-5-hydroxy-10-methyl-3,15-dioxo-4,5,13,15-tetrahydro-1H, 3H-oxepino chloride [3 ', 4': 6,7] indolizino [1,2-c] quinolin-12-ylmethyl] -4-methyl-hexahydropyridinium :

Un mélange de produit de l'étape 3.g (2,3 g; 7,7 mmol) et d'éthanol absolu (300 ml) est soumis pendant 2 minutes à des ultrasons. La suspension laiteuse obtenue est agitée et traitée par de l'acide chlorhydrique (solution 1N; 13,2 ml; 13,2 mmol) pour donner une solution jaune clair qui, au repos, forme un précipité de type gel. Le précipité est récupéré par filtration sur Büchner et lavé successivement avec de l'éthanol et de l'éther, puis séché sous pression réduite pour donner le produit du titre (2,1 g; 85 % de rendement).
RMN 1H (DMSO): 0,87 (m, 6H); 1,59 (m, 5H); 1,84 (q, 2H); 2,64 (s, 3H); 3,28 (dd, 2H); 3,45 (s, 2H); 4,93 (s, 2H); 5,47 (dd, 2H); 5,61 (s, 2H); 6,04 (pic large, 1H); 7,41 (s, 1H); 8,28 (s, 1H); 8,63 (s, 1H); 10,30 (pic large, 1H).
IR (KBr) : 1043, 1212, 1479, 1585, 1655, 1751 cm-1. A mixture of product from step 3.g (2.3 g; 7.7 mmol) and absolute ethanol (300 ml) is subjected for 2 minutes to ultrasound. The milky suspension obtained is stirred and treated with hydrochloric acid (1N solution; 13.2 ml; 13.2 mmol) to give a light yellow solution which, on standing, forms a gel-like precipitate. The precipitate is recovered by filtration on Büchner and washed successively with ethanol and ether, then dried under reduced pressure to give the title product (2.1 g; 85% yield).
1 H NMR (DMSO): 0.87 (m, 6H); 1.59 (m, 5H); 1.84 (q, 2H); 2.64 (s, 3H); 3.28 (dd, 2H); 3.45 (s, 2H); 4.93 (s, 2H); 5.47 (dd, 2H); 5.61 (s, 2H); 6.04 (broad peak, 1H); 7.41 (s, 1H); 8.28 (s, 1H); 8.63 (s, 1H); 10.30 (broad peak, 1H).
IR (KBr): 1043, 1212, 1479, 1585, 1655, 1751 cm -1 .

ÉTUDE PHARMACOLOGIOUE DES PRODUITS DE L'INVENTIONPHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Test sur la prolifération cellulaire.Cell proliferation test.

Cinq lignées de cellules tumorales sont utilisées dans cette étude : SW620 (adénocarcinome de colon humain), OVCAR-5 (adénocarcinome d'ovaire humain), PC-3 et DU 145 (lignée cellulaire de prostate humaine) et NCI-H69 (adénocarcinome de poumon humain). Ces lignées proviennent du NCI/Frederick Cancer Research and Development Center (Frederick, MD). Elles sont cultivées en milieu complet comprenant le milieu RMPI-1640 enrichi de 10 % de sérum de veau foetal et de 2 mM de L-Glutamine. Elles sont incubées à 37°C en atmosphère humide à 5 % de CO2. Les cellules adhérentes sont décollées par un traitement avec une solution à 0,25 % de trypsine et 0,2% d'EDTA (Worthington Biochemical Corp., Freehold, NJ) pendant 5 minutes à 37 °C. Le comptage des cellules se fait à l'aide d'un compteur Coulter Z1 (Coulter Corp., Hialeah, FL). La viabilité est évaluée en colorant les cellules avec de l'iodure de propidium puis en les dénombrant avec un cytomètre en flux EPICS Elite (Coulter).Five tumor cell lines are used in this study: SW620 (human colon adenocarcinoma), OVCAR-5 (human ovarian adenocarcinoma), PC-3 and DU 145 (human prostate cell line) and NCI-H69 (human adenocarcinoma human lung). These lines come from the NCI / Frederick Cancer Research and Development Center (Frederick, MD). They are cultured in complete medium comprising the RMPI-1640 medium enriched with 10% fetal calf serum and 2 mM L-Glutamine. They are incubated at 37 ° C in a humid atmosphere at 5% CO 2 . The adherent cells are detached by treatment with a 0.25% trypsin and 0.2% EDTA solution (Worthington Biochemical Corp., Freehold, NJ) for 5 minutes at 37 ° C. The cells are counted using a Coulter Z1 counter (Coulter Corp., Hialeah, FL). Viability is assessed by staining the cells with propidium iodide and then counting them with an EPICS Elite flow cytometer (Coulter).

Le composé de l'exemple 2 à tester est dissout à 5 mM dans une solution de N,N-diméthylacétamine (DMA, Aldrich). Les dilutions ultérieures sont effectuées avec du milieu de culture. Les concentrations molaires finales testées sont : 1.10-6, 2.10-7, 4.10-8, 8.10-9, 1,6.10-9, 3,2.10-10, 6,4.10-11, 1,28.10-11, 2,56.10-12, et 5,12.10-13. Chaque concentration est testée sur huit puits. Des contrôles sur l'influence du DMA ont été effectués sur toutes les lignées cellulaires. Il résulte de ces contrôles qu'à la concentration maximale utilisée (0,02 %) le DMA n'a pas d'effet. La doxorubicine aux concentrations de 1.10-7 M et 2.10-7 M est utilisée comme contrôle positif.The compound of Example 2 to be tested is dissolved at 5 mM in a solution of N, N-dimethylacetamine (DMA, Aldrich). Subsequent dilutions are made with culture medium. The final molar concentrations tested were: 1.10 -6 2.10 -7, -8 4.10 8.10 -9, -9 1.6.10, 3,2.10 -10, 6,4.10 -11, -11 1,28.10, 2,56.10 -12 , and 5,12.10 -13 . Each concentration is tested on eight wells. Checks on the influence of DMA were carried out on all the cell lines. It follows from these checks that at the maximum concentration used (0.02%) DMA has no effect. Doxorubicin at concentrations of 1.10 -7 M and 2.10 -7 M is used as a positive control.

Les cellules sont ensemencées à 5.103 cellules par puit sur une microplaque à 96 puits (Costar Corporation, Cambridge, MA). Les cellules sont incubées 24 h à 37 °C afin de permettre une reprise de la multiplication cellulaire. Le composé des exemples 2 et 3 à tester est ensuite ajouté aux concentrations indiquées ci-dessus et les cellules sont incubées à 37 °C en atmosphère humide à 5 % de CO2, pendant 3 jours pour les cellules adhérentes (SW620, OVCAR-5, PC-3 et DU 145) et pendant 5 jours pour les cellules en suspension (NCI-H69).The cells are seeded at 5.10 3 cells per well on a 96-well microplate (Costar Corporation, Cambridge, MA). The cells are incubated 24 h at 37 ° C to allow resumption of cell multiplication. The compound of Examples 2 and 3 to be tested is then added at the concentrations indicated above and the cells are incubated at 37 ° C. in a humid atmosphere at 5% CO 2 , for 3 days for the adherent cells (SW620, OVCAR-5 , PC-3 and DU 145) and for 5 days for cells in suspension (NCI-H69).

Les cellules adhérentes sont testées par la méthode SRB (décrite par L.V. Rubenstein, R.H. Shoemaker, K.D. Paull, R.M. Simon, S. Tosini, P. Skehan, D.A Scudiero., A. Monks, and M.R. Boyd "Comparison of in vitro anticancer-drug-screening data generated with tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines", J. Nat. Cancer Inst., 82:1113-1118, 1990). Après trois jours d'incubation le surnageant est éliminé et 200 µl RPMI-1640 exempt de sérum de veau foetal sont ajoutés. Les cellules sont fixées par addition de 50 µl d'acide trichloroacétique à 50 % (concentration finale d'acide trichloroacétique de 10 %) et incubées à 4 °C pendant 1 heure. Les puits sont lavés 5 fois avec de l'eau puis colorés par 50 µl d'une solution à 0,4 % de sulforhodamine B (SRB, Sigma) dans de l'acide acétique à 1 % à température ambiante pendant 10 minutes. La teinture est solubilisée avec 100 µl de tampon TRIS à 10 mM, pH 10, pendant environ 5 minutes avec agitation, les microplaques sont lues par spectrophotométrie à 570 nm.The adherent cells are tested by the SRB method (described by LV Rubenstein, RH Shoemaker, KD Paull, RM Simon, S. Tosini, P. Skehan, DA Scudiero., A. Monks, and MR Boyd "Comparison of in vitro anticancer- drug-screening data generated with tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines ", J. Nat. Cancer Inst ., 82 : 1113-1118, 1990). After three days of incubation, the supernatant is eliminated and 200 μl RPMI-1640 free of fetal calf serum is added. The cells are fixed by adding 50 μl of 50% trichloroacetic acid (final concentration of 10% trichloroacetic acid) and incubated at 4 ° C for 1 hour. The wells are washed 5 times with water and then stained with 50 μl of a 0.4% solution of sulforhodamine B (SRB, Sigma) in 1% acetic acid at room temperature for 10 minutes. The dye is dissolved with 100 μl of 10 mM TRIS buffer, pH 10, for approximately 5 minutes with stirring, the microplates are read by spectrophotometry at 570 nm.

Les cellules en suspension sont testées par la méthode XTT (décrite par D.A. Scudiero, R.H. Shoemaker, K.D. Paull, A. Monks, S. Tierney, T.H. Nofziger, M.J. Currens, D. Seniff et M.R. Boyd : "Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Research 48:4827-4833, 1988). Après incubation en présence du composé des exemples 2 et 3 à tester, le XTT [sel sodique du 2,3-bis(2-méthoxy-4-nitro-5-sulfophényl)-2H-tétrazolium-5-carboxanilide, (Sigma)] et le méthosulfate de phénazine (PMS, Sigma) en solution dans du tampon phosphate salin sont ajoutés aux cultures, et les cellules sont incubées pendant 4 heures à 37 °C dans une atmosphère à 5 % de CO2. Les concentrations finales de XTT et de PMS sont respectivement de 50 et 0,38 µg/puit. La production de formazan est stoppée par addition de 10 µl de dodécylsulfate de sodium à 10 % (Sigma) et l'absorbance est lue par spectrophotométrie à 450 nm avec un filtre de référence à 600-650 nm.The cells in suspension are tested by the XTT method (described by DA Scudiero, RH Shoemaker, KD Paull, A. Monks, S. Tierney, TH Nofziger, MJ Currens, D. Seniff and MR Boyd: "Evaluation of a soluble tetrazolium / formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines ", Cancer Research 48 : 4827-4833, 1988). After incubation in the presence of the compound of Examples 2 and 3 to be tested, the XTT [sodium salt of 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5-carboxanilide, (Sigma) ] and phenazine methosulfate (PMS, Sigma) in solution in saline phosphate buffer are added to the cultures, and the cells are incubated for 4 hours at 37 ° C. in an atmosphere at 5% CO 2 . The final concentrations of XTT and PMS are 50 and 0.38 µg / well, respectively. The production of formazan is stopped by adding 10 μl of 10% sodium dodecylsulfate (Sigma) and the absorbance is read by spectrophotometry at 450 nm with a reference filter at 600-650 nm.

Résultats : Results :

Les concentrations molaires des composés de l'exemple 2 inhibant de 50% la prolifération cellulaire sont compilées dans le tableau suivant : Lignée cellulaire Exemple 2 SW620 3.10-8 OVCAR-5 4.10-8 PC-3 3.10-8 DU 145 7.10-9 NCI-H69 1.10-9 The molar concentrations of the compounds of Example 2 which inhibit cell proliferation by 50% are compiled in the following table: Cell line Example 2 SW620 3.10 -8 OVCAR-5 4.10 -8 PC-3 3.10 -8 FROM 145 7.10 -9 NCI-H69 1.10 -9

Claims (9)

  1. Product characterized in that it has the formula (II) represented below
    Figure 00310001
    or in that it is the salts of the compound of formula (II).
  2. Product according to claim 1 characterized in that the salt of the compound of formula (II) is the compound of formula (III)
    Figure 00310002
  3. Product of general formula M represented below
    Figure 00320001
    in which R represents an ethyl radical.
  4. Preparation process for a product of general formula M represented below,
    Figure 00320002
    in which R represents the ethyl group,
    characterized in that it is constituted by the following successive stages:
    the racemic t-butyl ester represented below
    Figure 00320003
    is treated with trifluoroacetic acid for 18 hours at ambient temperature in order to produce the corresponding carboxylic acid;
    then the quinidine salt of the acid obtained previously is heated in isopropyl alcohol at a temperature greater than 30°C, before leaving the reaction medium to cool down to ambient temperature, so that the salt of one of the enantiomers of the above-mentioned acid crystallizes while the salt of the other enantiomer, the anion of which is represented below, remains in solution
    Figure 00330001
    the solution in isopropyl alcohol of the salt of the enantiomer which has not crystallized is concentrated and treated with hydrochloric acid and agitated, producing the compound of general formula A represented below
    Figure 00330002
    the compound of general formula A is then put in contact with palladium on damp carbon, then ammonium formate or formic acid is added to the mixture in order to produce the debenzylated product of general formula B represented below
    Figure 00330003
    then the compound of general formula B is cyclized by the action of dicyclohexylcarbodiimide in order to obtain the lactonic compound of general formula C represented below
    Figure 00340001
    finally, the -OCH3 group of the lactonic compound of general formula C is converted into carbonyl, by the action of sodium iodide and trimethylsilyl chloride, in order to obtain a compound of general formula M represented below.
    Figure 00340002
  5. As a medicament, a product according to claims 1 to 2, or any mixture of said products.
  6. Pharmaceutical composition containing, as active ingredient, at least one of the compounds of claim 5.
  7. Use of a compound according to claim 1 or 2, for the preparation of antitumoral medicaments.
  8. Use of a compound according to claim 1 or 2, for the preparation of antiviral medicaments.
  9. Use of a compound according to claim 1 or 2, for the preparation of antiparasitic medicaments.
EP98941567A 1997-08-29 1998-08-07 Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same Expired - Lifetime EP1007527B1 (en)

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